Coronin 1 regulates cognition and behavior through modulation of cAMP/protein kinase A signaling

PLoS Biol. 2014 Mar 25;12(3):e1001820. doi: 10.1371/journal.pbio.1001820. eCollection 2014 Mar.

Abstract

Cognitive and behavioral disorders are thought to be a result of neuronal dysfunction, but the underlying molecular defects remain largely unknown. An important signaling pathway involved in the regulation of neuronal function is the cyclic AMP/Protein kinase A pathway. We here show an essential role for coronin 1, which is encoded in a genomic region associated with neurobehavioral dysfunction, in the modulation of cyclic AMP/PKA signaling. We found that coronin 1 is specifically expressed in excitatory but not inhibitory neurons and that coronin 1 deficiency results in loss of excitatory synapses and severe neurobehavioral disabilities, including reduced anxiety, social deficits, increased aggression, and learning defects. Electrophysiological analysis of excitatory synaptic transmission in amygdala revealed that coronin 1 was essential for cyclic-AMP-protein kinase A-dependent presynaptic plasticity. We further show that upon cell surface stimulation, coronin 1 interacted with the G protein subtype Gαs to stimulate the cAMP/PKA pathway. The absence of coronin 1 or expression of coronin 1 mutants unable to interact with Gαs resulted in a marked reduction in cAMP signaling. Strikingly, synaptic plasticity and behavioral defects of coronin 1-deficient mice were restored by in vivo infusion of a membrane-permeable cAMP analogue. Together these results identify coronin 1 as being important for cognition and behavior through its activity in promoting cAMP/PKA-dependent synaptic plasticity and may open novel avenues for the dissection of signal transduction pathways involved in neurobehavioral processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Butyrolactone / analogs & derivatives
  • 4-Butyrolactone / genetics
  • Animals
  • Behavior, Animal*
  • Brain / metabolism
  • Brain / pathology
  • Cognition / physiology*
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Humans
  • Memory
  • Mice
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Microfilament Proteins / physiology*
  • Signal Transduction
  • Social Behavior

Substances

  • Microfilament Proteins
  • coronin
  • coronin proteins
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • 4-Butyrolactone

Grant support

This work was supported by the Swiss National Science Foundation, the Canton of Basel, the Optimus Foundation, the ETH Zürich within the framework of the National Center for Competence in Research in Structural Biology Program, the Agence Nationale pour la Recherche, and the Novartis Research Foundation. Michael Stiess is a recipient of an HFSP Fellowship, Michael Stiess and Somdeb BoseDasgupta are recipients of an EMBO Long Term Fellowship, Rajesh Jayachandran is a recipient of a Cloetta Medical Fellowship, and Despina Moshous received a Robert A. Good/Jeffrey Modell Fellowship in Transplantation and Immunodeficiency. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.